SUBSPECIALTY NEWS

18.3% of CATT Patients Developed GA

Study implicates anti-VEGF therapy.

BY JERRY HELZNER, SENIOR EDITOR

■ One of the great unresolved questions to come out of the recent, large-scale CATT trial comparing the safety and efficacy of ranibizumab (Lucentis, Genentech, South San Francisco, CA) with bevacizumab (Genentech) was whether repeated dosing of these anti-VEGF therapies over a period of time could trigger geographic atrophy (GA) in patients who had shown no signs of GA at baseline.

A number of respected retina specialists, including Philip Rosenfeld, MD, PhD, of Bascom Palmer Eye Institute in Miami, FL, have been leaning toward the position that repeated anti-VEGF over time can trigger GA. However, Dr. Rosenfeld and others wanted to see additional studies that might provide confirmation of this hypothesis.

Now, a team of researchers led by Juan E. Grunwald, MD, of the University of Pennsylvania, has published a study of 1,024 CATT patients whose color fundus photos or fluorescein angiograms showed no visible signs of GA at enrollment. After two years, the researchers found that GA had developed in 187 patients, or 18.3% of the cohort being studied.

While the researchers noted several possible factors that could have contributed to the development of GA, including lower visual acuity at baseline, retinal angiomatous proliferation, and foveal intraretinal fluid, they also implicated monthly dosing and the use of ranibizumab in GA development. They concluded that “anti-VEGF therapy may have a role in the development of GA.”

“This study confirms the suspicions previously raised,” says Dr. Rosenfeld. “This new analysis is all very consistent with prior reports. The information I want to see is whether the appearance and growth of GA in the HARBOR study was influenced by monthly dosing or the higher Lucentis dose. These are very important data.”

REFERENCE

Grunwald JE, Daniel E, Huang J, et al. Risk of geographic atrophy in the Comparison of Age-related Macular Degeneration Treatments Trials (CATT). Ophthalmology. 2013 Sep 30. [Epub ahead of print]

Genentech Not Resting on Lucentis Laurels

Company readying new initiatives in retina therapy.

BY JERRY HELZNER, SENIOR EDITOR

■ For those who have been waiting to hear how anti-VEGF pioneer Genentech (Roche, South San Francisco, CA) intends to counter the promising initiatives in combination retinal disease therapies brought forward by its rivals, your wait is over.

In a wide-ranging interview with Retinal Physician, Gary Sternberg, MD, therapeutic area head for ophthalmic medical affairs for Genentech, described a bispecific, single-molecule combination that the company believes is on schedule to move into a phase 1 clinical trial in 2014. As Dr. Sternberg describes it, the combination will contain an anti-VEGF element and another targeted therapeutic that could be an anti-PDGF agent or something else that the company may choose for the trial.

“This combination will not be coformulated and will be delivered with a single injection,” Dr. Sternberg says. “It will act in the eye with high potency but, upon entering the systemic circulation, be rapidly eliminated with low systemic exposure to the drug.”

Dr. Sternberg says the combination is based on “elegant technology” and is intended to improve efficacy, which may possibly decrease the number of injections and monitoring visits that a patient will require in the course of a year.

DELIVERY SYSTEMS EXPLORED

While Genentech is developing its combination drug, it is also actively exploring a number of novel concepts in drug delivery, including sustained- release formats. In this area, Genentech has been working with ForSightVision4 (Menlo Park, CA) and is looking at other delivery concepts that it believes have potential.

“For drug delivery, we are taking multiple shots on goal,” says Dr. Sternberg. “New methods of drug delivery are a high priority for us.”

Another priority for the company is developing personalized medicines that can be tailored to specific patients or subsets of patients.

“We have a strong commitment to developing the right drugs for the right patients, whether that is based on genetic markers or disease-specific factors,” Dr. Sternberg says. “In our recent phase 2 MAHALO trial for geographic atrophy [GA], we were able to identify a subset of patients with a specific biomarker whose progression rate was reduced by more than double the rate of the overall study population.”

On the question of whether heavy or prolonged dosing of anti-VEGF can trigger GA, Dr. Sternberg says Genentech believes the question warrants further study and is looking closely at the company’s HARBOR trial, which had monthly and asneeded arms with both a 2-mg and an 0.5-mg dose.

“We are studying all the HARBOR data, including the findings from fellow eyes, to determine whether there was GA and, if there was, whether this was underlying GA or if the GA might have been drug or regimen-induced.”

LOOKING AT THE FUTURE

Asked to predict how retinal disease would be treated 10 years from now, Dr. Sternberg says he believes the primary delivery system would still be intravitreal injections, which have been proven safe. However, he believes that with newly developed therapies, probably combinations or sustained delivery, patients would only need two or three injections a year and far fewer monitoring visits.

Adds Dr. Sternberg: “Genentech is exploring multiple research opportunities in the ophthalmic space and plans to play a significant role in the development of ophthalmic treatments for years to come.”

Allegro’s Key Drug in Two New Trials

Integrin peptide therapy targets wet AMD and VMT.

BY JERRY HELZNER, SENIOR EDITOR

■ Moving ahead on two fronts, Allegro Ophthalmics (San Juan Capistrano, CA) has advanced its integrin peptide inhibitor ALG-1001 into two new phase 2 clinical trials, one targeting wet AMD and the other symptomatic vitreomacular traction (VMT). The two studies were announced after the FDA approved Allegro’s Investigational New Drug application.

ALG-1001 is unique in that it primarily targets the mechanism in the eye that produces VEGF rather than just targeting the VEGF itself. In disrupting VEGF production at its source, Allegro believes that ALG-1001 can achieve a more durable response, with visual improvement lasting up to six months. ALG-1001 monotherapy has demonstrated this capability in previous phase 1 trials for wet AMD and DME. In addition, Allegro believes that ALG-1001 could be used in combination with anti-VEGF agents to produce even better results and has initiated one such phase 1b/2a trial for the treatment of DME

ALG-1001 has also shown promise in the resolution of VMT in a phase 1 trial of end-stage DME patients.

“There were 15 subjects in the study, all receiving three monthly injections of ALG-1001 as monotherapy and then followed for three months off-treatment,” says Marc Kirshbaum, Allegro COO. “There was a 90-day washout period for either anti-VEGF or laser therapy. Of the 15 subjects enrolled in the study, 11 patients did not have a total PVD [posterior vitreous detachment] at baseline. Of these 11 patients, six developed a total PVD during the study, equaling 55%. These were all end-stage DME subjects for whom obtaining such a release is notoriously difficult.”

Replicating these results in larger, later-stage clinical trials would make ALG-1001 a competitor to Jetrea (ThromboGenics, Iselin, NJ), the only currently approved pharmacologic treatment for symptomatic VMT.

“We are extremely pleased with the FDA approval [of the new clinical trials], which validates our preclinical data, multiple phase 1 study results, and phase 2 clinical study design,” says Vicken Karageozian, MD, cofounder and chief technical officer of Allegro. “We’ve rapidly and methodically gone from compound discovery to phase 2 clinical trials. We are optimistic that this drug will continue to show efficacy and provide meaningful therapeutic benefit to patients with vascular eye diseases, such as wet AMD and VMT.”